Is pre-diabetes a predictor of events in patients with atrial fibrillation?

BACKGROUND: Diabetes mellitus (DM) increases the probability of presenting atrial fibrillation (AF) and it is a predictor of its ischemic stroke. There is limited information of the association between glycated hemoglobin (HbA1c) levels and ischemic, embolic or bleeding events in patients with pre-DM and AF. METHODS: To investigate whether the presence of pre-DM in patients with AF predicts ischemic or bleeding events, myocardial infarction or mortality, we performed a retrospective study with a final cohort of 2993 non-diabetic patients with AF and data of glycated hemoglobin (HbA1c). We divided the cohort in two groups: those with normal glucose (n = 1351) and those with pre-diabetes (n = 1642). Incidence rates were calculated as the number of events per 100 person-years and were then compared between groups. Competitive hazard regression analysis for non-fatal events(death as the competing event) and conventional Cox regression for mortality were performed. RESULTS: There was not difference between groups for incidence rates of the different events per 100 person-years. Even considering HbA1c as continuous variable, the unadjusted analysis showed no relation between levels of HbA1c and more risk of events. This association remained not significant after adjustment for CHA2DS2-VASc score, HAS-BLED score and anticoagulation therapy. CONCLUSION: In this study of 2993 non-diabetic patients with new-onset AF, we have not found an association between HbA1c and worse prognosis when it is in the range of pre-diabetes.

Use of Darvadstrocel (Allogenic Stem Cell Therapy) for Crohn's Fistulas in Real Clinical Practice: The National Project to Implement Mesenchymal Stem Cell for the Treatment of Perianal Crohn's Fistula (the PRIME Study).

BACKGROUND: Perianal fistulas may affect 15% to 50% of patients with Crohn's disease. Treatment is complex, requiring a multidisciplinary approach. Darvadstrocel (allogenic mesenchymal cells obtained from lipoaspirates) was approved in 2018 by the European and Spanish Agencies of Medicines and Medical Products as a treatment for fistulas in Crohn's disease. Recent guidelines from the European Crohn's and Colitis Organisation and Spanish Working Group on Crohn's Disease and Ulcerative Colitis state that darvadstrocel is effective with a favorable safety profile and a strong level of evidence (n = 2). OBJECTIVE: Presenting real-world effectiveness data for darvadstrocel in a Spanish population. DESIGN: Observational retrospective cohort study with prospective data gathering. SETTINGS: The study was conducted at 14 institutions in Spain. PATIENTS: From November 2019 to April 2022, all patients (n = 73) treated with darvadstrocel in these institutions were included, fulfilling the following criteria: 1) complex fistula/s in a patient with Crohn's disease; 2) failure of conventional and antitumor necrosis factor treatment; and 3) the absence of collections of >2 cm confirmed by pelvic MRI at the time of surgery. INTERVENTIONS: Darvadstrocel treatment. MAIN OUTCOME MEASURES: Clinical response (closure of 50% or more of external openings), complete clinical closure (100% of external openings), and radiological closure (no fluid collection >2 cm, edema, or inflammation) evaluated 6 months after treatment. RESULTS: Clinical response was observed in 63 patients (86.3%), complete clinical closure in 50 patients (68.5%), and radiological closure in 45 patients (69.2%). Combined clinical and radiological response was observed in 41 patients (63.1%). Not all clinically healed patients had radiological closure, and vice versa. No serious adverse events were reported. LIMITATIONS: Retrospective nature of the study. CONCLUSIONS: Study results were consistent with those reported in previous clinical trials, real-world efficacy findings from the INSPIRE study (assessing darvadstrocel effectiveness in Europe, Israel, Switzerland, United Kingdom, and Japan), and previously published literature. Darvadstrocel was effective and demonstrated a favorable safety profile when used in normal clinical practice for the treatment of fistulas in Crohn's disease. See Video Abstract . USO DE DARVADSTROCEL TERAPIA CON CLULAS MADRE ALOGNICAS PARA FSTULA EN ENFERMEDAD DE CROHN EN LA PRCTICA CLNICA REAL EL PROYECTO NACIONAL PARA IMPLEMENTAR DE CLULAS MADRE MESENQUIMALES PARA EL TRATAMIENTO DE LA FSTULA DE CROHN PERIANAL EL ESTUDIO PRIME: ANTECEDENTES:Las fístulas perianales pueden afectar entre el 15 y el 50% de los pacientes con enfermedad de Crohn. El tratamiento es complejo y requiere un enfoque multidisciplinario. El darvadstrocel (células mesenquimales alogénicas obtenidas a partir de lipoaspirados) fue aprobado en 2018 por las Agencias Europea y Española de Medicamentos y Productos Sanitarios como tratamiento de las fístulas en la EC. Las recientes directrices de la Organización Europea de Crohn y Colitis y del Grupo de Trabajo Español sobre la Enfermedad de Crohn y Colitis Ulcerosa afirman que darvadstrocel es eficaz con un perfil de seguridad favorable y un sólido nivel de evidencia (2).OBJETIVO:Presentar datos de eficacia real de darvadstrocel en población española.DISEÑO:Estudio de cohorte retrospectivo observacional con recopilación prospectiva de datos.ESCENARIO:14 instituciones.PACIENTES:Desde noviembre de 2019 hasta abril de 2022, se incluyeron todos los pacientes (73) tratados con darvadstrocel en estas instituciones, que cumplieron los siguientes criterios: 1) fístula/s compleja/s en un paciente con enfermedad de Crohn; 2) fracaso del tratamiento convencional y anti factor de necrosis tumoral; 3) ausencia de colecciones > 2 cm confirmada por resonancia magnética pélvica en el momento de la cirugía.INTERVENCIONES:Tratamiento con Darvadstrocel.PRINCIPALES MEDIDAS DE RESULTADO:Respuesta clínica (cierre de ≥50% de las aberturas externas), cierre clínico completo (100% de las aberturas externas) y cierre radiológico (sin acumulación de líquido >2 cm, sin edema ni inflamación) evaluados 6 meses después del tratamiento.RESULTADOS:Se observó respuesta clínica en 63 pacientes (86.3%), cierre clínico completo en 50 pacientes (68.5%) y cierre radiológico en 45 pacientes (69.2%). Se observó respuesta clínica y radiológica combinada en 41 pacientes (63.1%). No todos los pacientes clínicamente curados tuvieron cierre radiológico y viceversa. No hubo eventos adversos graves reportados.LIMITACIONES:Estudio retrospectivoCONCLUSIONES:Los resultados del estudio fueron consistentes con los informados en ensayos clínicos anteriores, los hallazgos de eficacia en el mundo real del estudio INSPIRE (que evalúa la efectividad de darvadstrocel en Europa, Israel, Suiza, el Reino Unido y Japón) y la literatura publicada anteriormente. Darvadstrocel fue eficaz y demostró un perfil de seguridad favorable cuando se utiliza en la práctica clínica habitual para el tratamiento de fístulas en la enfermedad de Crohn. (Traducción-Dr. Jorge Silva Velazco ).

Patient engagement and satisfaction with early phase cell therapy clinical trials at a tertiary inflammatory bowel disease center.

Several clinical trials are underway investigating cell and gene therapy, and while these trials are meant to significantly impact patient care, they rely on patient engagement and participation. Unfortunately, clinical trials generally require extensive commitment by subjects. While several studies are using validated surveys to measure patient-reported outcomes, there is a lack of characterization of the patient experience as a subject in these trials. As such, we surveyed mesenchymal stromal cell (MSC) trial participants to understand their perspective. We found that there exists a reliance on one's gastroenterologist and colorectal surgeons for trial introduction and that time and cost were the main barriers to participation. Overall, participants demonstrated high satisfaction with MSC trial participation, but future protocols could incorporate increased use of virtual appointments to optimize patient experience.

Liver fibrosis and outcomes of atrial fibrillation: the FIB-4 index.

BACKGROUND AND AIMS: Liver diseases play an important role in the development and progression of atrial fibrillation (AF). The Fibrosis-4 (FIB-4) index is a non-invasive score recommended for detecting liver fibrosis. Since the association between liver fibrosis and outcomes of AF patients is still not well defined, we aim to analyze prognosis impact of FIB-4 index in those patients. METHODS: A retrospective population-based cohort study was performed with 12,870 unselected patients from a single health area in Spain with AF from 2014 to 2019. Cox regression models were used to estimate the association of FIB-4 index with mortality. The association with ischemic stroke (IS), major bleeding (MB), acute myocardial infarction (AMI), and heart failure (HF) was assessed by competing risk analysis. RESULTS: A total of 61.1%, 22.0%, and 16.9% were classified as low, moderate and high risk of liver fibrosis according to FIB-4 index, respectively. During a mean follow-up of 4.5 ± 1.7 years, FIB-4 index was associated with mortality (adjusted HR 1.04; 95% CI 1.01-1.06; p = 0.002), MB and HF (adjusted sHR 1.03, 95% CI 1.01-1.04; p = 0.004), but not with IS or with AMI. The association between FIB-4 and MB was only found in patients treated with vitamin K antagonists, not in patients on direct oral anticoagulants. CONCLUSIONS: The FIB-4 index, a non-invasive scoring method for evaluating liver fibrosis, is independently associated with all-cause mortality, MB and HF in patients with AF, suggesting that it may be useful as a risk assessment tool to identify adverse outcomes in patients with AF.

A phase IB/IIA study of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of rectovaginal fistulizing Crohn's disease.

BACKGROUND: Crohn-related rectovaginal fistulas are notoriously difficult to treat. Studies of mesenchymal stem cells for the treatment of perianal Crohn fistulizing disease have largely excluded rectovaginal fistulas. The aim of this study was to determine the safety and efficacy of mesenchymal stem cells for refractory rectovaginal fistulizing Crohn disease. METHODS: A phase IB/IIA randomized control trial was performed in a 3:1, single-blinded study. Patients included were adult women with an anovaginal/rectovaginal fistula in the setting of Crohn disease. Seventy-five million mesenchymal stem cells were administered with a 22G needle after curettage and primary closure of the fistula tract at day 0 and month 3. Adverse and serious adverse events were recorded at post-procedure day 1, week 2, week 6, month 3, month 6, and month 12, along with clinical healing, magnetic resonance imaging, and patient-reported outcomes. RESULTS: A total of 19 patients were enrolled and treated-15 treatment and 4 control. There were no adverse or serious adverse events related to mesenchymal stem cell therapy. At 6 months, 50% of the treatment group and 0% of the control had complete clinical and radiographic healing; 91.7% of the treatment group had improvement at 6 months with only one patient having a lack of response, whereas only 50% of the control group had improvement at 6 months. CONCLUSION: Bone marrow-derived mesenchymal stem cells offer a safe alternative treatment approach for rectovaginal fistulas in the setting of Crohn disease. Complete healing was achieved in half of the patients.

Treatment effect of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of fistulizing Crohn's disease are durable at 12 months.

BACKGROUND: Mesenchymal stem cells have been administered via direct injection to treat perianal Crohn's fistulizing disease. We herein sought to determine the safety and durability of treatment response to 12 months with 3 individual phase IB/IIA clinical trials of mesenchymal stem cells for refractory perianal, rectovaginal, and ileal pouch fistulas in the setting of Crohn disease. METHODS: Three phase IB/IIA randomized placebo-controlled single-blinded clinical trials were performed for (1) perianal fistulas, (2) rectovaginal fistula, and (3) ileal pouch in situ with anovaginal and/or perianal fistulas. Bone marrow-derived mesenchymal stem cells (75 million in 7.5 mL) were injected at the time of exam under anesthesia on day 0 and month 3. Outcome measures were adverse events and combined clinical and pelvic magnetic resonance imaging healing at month 6 and month 12. RESULTS: Across all 3 trials, 64 patients were enrolled; 49 were treatment and 15 were control. At 6 months, combined clinical and radiographic healing was achieved in 83.3%, 33.3%, and 30.8% of the perianal, rectovaginal, and pouch fistula treatment cohorts, respectively. At 12 months, the treatment response was durable, with 67.7% of perianal, 37.5% of rectovaginal, and 46.2% of peripouch fistulas maintaining complete clinical and radiographic healing. Two patients in the perianal fistula control cohort achieved combined clinical and radiographic healing at 12 months, whereas 0% of rectovaginal and pouch control patients healed. CONCLUSION: Bone marrow-derived mesenchymal stem cells offer a safe and effective alternative treatment approach for severe perianal, rectovaginal, and peripouch fistulizing Crohn's disease. Treatment results are durable at 12 months.

Salvage Surgery: An Effective Therapy in the Management of Ileoanal Pouch Prolapse.

BACKGROUND: Restorative proctocolectomy with IPAA is the surgical treatment of choice for patients requiring surgery for IBD and, less frequently, for other pathologies. Pouch prolapse is a rare complication that compromises pouch function and negatively affects patients' quality of life. OBJECTIVE: This study aimed to describe our experience from a single high-volume center in this infrequent condition. DESIGN: Restrospective cohort study of a prospectively maintained, Institutional Review Board-approved database. SETTINGS: All consecutive eligible patients with IPAA and pouch prolapse were identified from 1990 to 2021. PATIENTS: Patients with full-thickness prolapse treated by pouch pexy were included. INTERVENTIONS: Pouch pexy (with/without mesh). MAIN OUTCOME MEASURES: Success rate of pouch pexy, defined as no recurrence of prolapse. RESULTS: A total of 4791 patients underwent IPAA; 7 (0.1%) were diagnosed with full-thickness prolapse. An additional 18 patients who underwent IPAA and had full-thickness prolapse were referred from outside institutions. Among 25 included patients, 16 (64.0%) were women, and the overall mean age was 35.6 ± 13.4 years. The time interval from initial pouch formation to prolapse was 4.2 (interquartile range, 1.1-8.5) years. Nine patients (36.0%) underwent previous treatment for prolapse. All patients presented with symptoms and physical examination compatible with full-thickness prolapse. Twenty patients (80.0%) underwent surgical pouch pexy without mesh and 5 (20.0%) had pouch pexy with mesh placement. A diverting ileostomy was performed in 1 patient (4.0%) before pouch pexy and in 8 patients (32.0%) at the time of surgical prolapse correction. After surgery, recurrent prolapse was noted in 3 patients (12.0%) at a median of 6.9 (interquartile range, 5.2-8.3) months. LIMITATIONS: Retrospective study, small sample size thus prone to selection, and referral biases, which may limit the generalizability of our findings. CONCLUSION: Pouch prolapse can be effectively treated with salvage surgery. Surgical intervention is safe and provides acceptable outcomes. See Video Abstract. CIRUGA DE RESCATE UNA TERAPIA EFICAZ EN EL MANEJO DEL PROLAPSO DE LA BOLSA ILEOANAL: ANTECEDENTES:La proctocolectomía restauradora con anastomosis reservorio ileoanal es el tratamiento quirúrgico de elección para aquellos pacientes que requieren cirugía por enfermedad inflamatoria intestinal y, con menor frecuencia, por otras patologías. El prolapso de la bolsa es una complicación rara que compromete la función de la bolsa y afecta de manera negativa la calidad de vida de los pacientes.OBJETIVO:Describir nuestra experiencia de un solo centro de alto volumen en esta condición poco frecuente.DISEÑO:Estudio de cohorte retrospectivo de una base de datos mantenida prospectivamente aprobada por el IRB.AJUSTES/PACIENTES:Fueron identificados y elegibles de manera consecutiva todos los pacientes con anastomosis de bolsa ileoanal y prolapso de bolsa entre 1990 y 2021. Se incluyeron pacientes con prolapso de bolsa de espesor total tratados con pexia.INTERVENCIONES:Pexia de la bolsa (con/sin malla).PRINCIPALES MEDIDAS DE RESULTADO:Tasa de éxito de la pexia de la bolsa, definida como ausencia de recurrencia del prolapso.RESULTADOS:Un total de 4.791 pacientes fueron sometidos a anastomosis de bolsa ileoanal; siete (0,1%) fueron diagnosticados con prolapso de espesor total. Otros 18 pacientes con anastomosis de reservorio ileoanal fueron derivados de instituciones externas. De entre los 25 pacientes incluidos, 16 (64,0 %) eran mujeres y la edad media promedio fue de 35,6+/-13,4 años. El intervalo de tiempo desde la creación inicial de la bolsa hasta el prolapso fue de 4,2 (IQR 1,1-8,5) años. Nueve (36,0 %) pacientes fueron sometidos a tratamiento previo para el prolapso (fisioterapia n = 4, pexia de la bolsa n = 2, pexia de la bolsa con malla n = 2, resección de la mucosa n = 1). Todos los pacientes presentaron síntomas y exploración física compatibles con prolapso de espesor total. Veinte (80,0%) pacientes se sometieron a pexia de bolsa quirúrgica sin malla y cinco (20,0%) se sometieron a pexia de bolsa con colocación de malla. Se realizó una ileostomía de derivación en un (4,0%) paciente antes de la pexia de la bolsa y en ocho (32,0%) pacientes en el momento de la corrección quirúrgica del prolapso. Posterior a la cirugía, se observó prolapso recurrente en tres pacientes (12,0 %) con una mediana de 6,9 (IQR 5,2-8,3) meses.LIMITACIONES:Estudio retrospectivo, pequeño tamaño de muestra, por lo tanto, propenso a sesgos de selección y referencia que pueden limitar la generalización de nuestros hallazgos.CONCLUSIÓN:El prolapso de la bolsa ileoanal puede tratarse de manera efectiva mediante la cirugía de rescate. La intervención quirúrgica es segura y proporciona resultados aceptables. (Traducción-Dr. Mauricio Santamaria ).

Surgical Options for the Treatment of Perianal and Anovaginal Fistulas in the Setting of Ileoanal Pouch Crohn's Disease: Experience of a Tertiary Center.

BACKGROUND: The leading cause of pouch failure following ileal pouch-anal anastomosis are peri-pouch fistulas and pelvic sepsis. OBJECTIVE: Determine the overall efficacy of current surgical therapy for the treatment of perianal and anovaginal fistulizing disease related to Crohn's disease phenotype of the pouch. DESIGN: Retrospective cohort study of a prospectively maintained, IRB-approved database. SETTINGS/PATIENTS: Ninety-one (2.3%) patients of 3058 patients with an original diagnosis of ulcerative colitis who underwent proctocolectomy with ileal pouch-anal anastomosis between 2000 and 2021 at the Cleveland Clinic and underwent postoperative surgery for Crohn's-related perianal disease. INTERVENTIONS: Two hundred thirty-one operations for perianal or anovaginal fistula(s). MAIN OUTCOME AND MEASURES: Healing rate of surgical therapy for peri-pouch fistulizing disease, impact of recurrent interventions on outcomes, and predictors of surgical failure. RESULTS: Overall mean age was 39.1 (± 11.6) years, with a BMI of 25.3 (± 6.3) kg/m2. More than half of the patients were female (n = 52, 57.1%). Sixty-three patients (69.2%) had a perianal fistula, 25 (27.5%) had an anovaginal fistula, and 3 (3.3%) patients had both. Overall success rate for healing was 59.3% (n = 54/91) at a mean follow-up of 6.4 (± 4.8) years. Seventeen (18.7%) patients underwent a concomitant diverting loop ileostomy. Among them, eight (47.0%) patients had the ileostomy closure after a mean time of 9.7 (± 2.8) months. In the multivariable logistic regression model, patients who had seton insertions in any operation were significantly less likely to heal (OR 0.11 95%, CI 0.03-0.43, p = 0.001). Overall pouch failure rate was 12.1%. LIMITATIONS: Retrospective single-center study which lacks a control arm and consistent long-term follow-up specific to a population-based dataset. CONCLUSIONS: Pouch patients who develop perianal disease are difficult to treat, sometimes requiring pouch excision. However, when medical treatment alone is not effective, a multidisciplinary approach including surgical intervention can result in complete fistula healing in more than half of the cases.

Predictive value of bleeding risk scores in elderly patients with atrial fibrillation and oral anticoagulation.

BACKGROUND: The predictive value of bleeding risk scores for atrial fibrillation in older patients is not as well known. The goal of this study was to evaluate the predictive value of HASBLED, ORBIT and ATRIA for major bleeding (MB) and intracranial hemorrhage (ICH) in patients ≥ 75 years with atrial fibrillation and oral anticoagulation (OAC). METHODS: A retrospective unicenter study including patients ≥ 75 years with atrial fibrillation (AF) and OAC. A total of 7613 patients ≥ 75 years with AF and OAC included between 2014 and 2018 (registry: NCT04364516). We analyzed the discriminative value of HASBLED, ATRIA and ORBIT scores for bleeding endpoints (major bleeding as primary endpoint and intracerebral hemorrhage as secondary). Cox regression was used to predict major bleeding with each scale and also for searching other variables potentially predictor of major bleeding. Model discrimination was assessed using Harrell's C-statistic. Calibration was assessed with goodness-of-fit test proposed by Gronnesby and Borgan. RESULTS: During a mean follow up of 4.0 years (IQR: 2.4-5.7 years), 729 patients developed MB (2.61 per 100 patients/year) and 243 patients developed ICH (0.85 per 100 patients/year). Three scores showed a low discrimination for major bleeding, being ORBIT the best (HASBLED C statistic = 0.557; ATRIA C statistic = 0.568; ORBIT C statistic = 0.595) and also a low discrimination for ICH (HASBLED C statistic = 0.509; ATRIA C statistic = 0.522; ORBIT C statistic = 0.526). Among the variables that are part of the scores and other baseline characteristics, after multivariable adjustment only sex (male), dementia, prior admission for bleeding, anemia and liver disease were found as a predictors of MB. CONCLUSIONS: In older patients under oral anticoagulation with atrial fibrillation, the risk scores HASBLED, ATRIA and ORBIT showed a weak discrimination for major bleeding and intracranial hemorrhage. Therefore, other better alternatives should be evaluated for this purpose.

Validation of a Pathological Score for the Assessment of Bronchial Biopsies in Severe Uncontrolled Asthma: Beyond Blood Eosinophils

Background: Blood eosinophil count (BEC) is currently used as a surrogate marker of T2 inflammation in severe asthma but its relationship with tissue T2-related changes is elusive. Bronchial biopsy could add reliable information but lacks standardization. Objectives: To validate a systematic assessment of the bronchial biopsy for the evaluation of severe uncontrolled asthma (SUA) by standardizing a pathological score. Methods: A systematic assessment of submucosal inflammation, tissue eosinophilic count/field (TEC), goblet cells hyperplasia, epithelial changes, basement membrane thickening, prominent airway smooth muscle and submucosal mucous glands was initially agreed and validated in representative bronchial biopsies of 12 patients with SUA by 8 independent pathologists. In a second phase, 62 patients with SUA who were divided according to BEC≥300cells/mm3 or less underwent bronchoscopy with bronchial biopsies and the correlations between the pathological findings and the clinical characteristics were investigated. Results: The score yielded good agreement among pathologists regarding submucosal eosinophilia, TEC, goblet cells hyperplasia and mucosal glands (ICC=0.85, 0.81, 0.85 and 0.87 respectively). There was a statistically significant correlation between BEC and TEC (r=0.393, p=0.005) that disappeared after correction by oral corticosteroids (OCS) use (r=0.170, p=0.307). However, there was statistically significant correlation between FeNO and TEC (r=0.481, p=0.006) that was maintained after correction to OCS use (r=0.419, p=0.021). 82.4% of low-BEC had submucosal eosinophilia, 50% of them moderate to severe. Conclusion: A standardized assessment of endobronchial biopsy is feasible and could be useful for a better phenotyping of SUA especially in those receiving OCS. (AU)

Time Interval Between the End of Neoadjuvant Therapy and Elective Resection of Locally Advanced Rectal Cancer in the CRONOS Study.

Importance: The treatment for extraperitoneal locally advanced rectal cancer (LARC) is neoadjuvant therapy (NAT) followed by total mesorectal excision (TME). Robust evidence on the optimal time interval between NAT completion and surgery is lacking. Objective: To assess the association of time interval between NAT completion and TME with short- and long-term outcomes. It was hypothesized that longer intervals increase the pathologic complete response (pCR) rate without increasing perioperative morbidity. Design, Setting, and Participants: This cohort study included patients with LARC from 6 referral centers who completed NAT and underwent TME between January 2005 and December 2020. The cohort was divided into 3 groups depending on the time interval between NAT completion and surgery: short (≤8 weeks), intermediate (>8 and ≤12 weeks), and long (>12 weeks). The median follow-up duration was 33 months. Data analyses were conducted from May 1, 2021, to May 31, 2022. The inverse probability of treatment weighting method was used to homogenize the analysis groups. Exposure: Long-course chemoradiotherapy or short-course radiotherapy with delayed surgery. Main outcome and Measures: The primary outcome was pCR. Other histopathologic results, perioperative events, and survival outcomes constituted the secondary outcomes. Results: Among the 1506 patients, 908 were male (60.3%), and the median (IQR) age was 68.8 (59.4-76.5) years. The short-, intermediate-, and long-interval groups included 511 patients (33.9%), 797 patients (52.9%), and 198 patients (13.1%), respectively. The overall pCR was 17.2% (259 of 1506 patients; 95% CI, 15.4%-19.2%). When compared with the intermediate-interval group, no association was observed between time intervals and pCR in short-interval (odds ratio [OR], 0.74; 95% CI, 0.55-1.01) and long-interval (OR, 1.07; 95% CI, 0.73-1.61) groups. The long-interval group was significantly associated with lower risk of bad response (tumor regression grade [TRG] 2-3; OR, 0.47; 95% CI, 0.24-0.91), systemic recurrence (hazard ratio, 0.59; 95% CI, 0.36-0.96), higher conversion risk (OR, 3.14; 95% CI, 1.62-6.07), minor postoperative complications (OR, 1.43; 95% CI, 1.04-1.97), and incomplete mesorectum (OR, 1.89; 95% CI, 1.02-3.50) when compared with the intermediate-interval group. Conclusions and Relevance: Time intervals longer than 12 weeks were associated with improved TRG and systemic recurrence but may increase surgical complexity and minor morbidity.

Multiple clonal transmissions of clinically relevant extended-spectrum beta-lactamase-producing Escherichia coli among livestock, dogs, and wildlife in Chile.

OBJECTIVES: Extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-E. coli) are a main cause of human deaths associated with antimicrobial resistance (AMR). Despite hundreds of reports of the faecal carriage of ESBL-E. coli in domestic and wild animals, the dynamics of its circulation remains poorly understood. METHODS: We used whole genome sequencing of 19 ESBL-E. coli previously isolated in the same local setting from dogs, livestock, and a wild rodent in Central Chile to assess potential cross-species transmission of ESBL-E. coli. RESULTS: Isolates harboured a large number of AMR (n = 95) and virulence (n = 45) genes, plasmids replicons (n = 24), and E. coli sequence types including top extraintestinal pathogenic E. coli ST410, ST58, ST88, and ST617. Almost identical clones (<50 single nucleotide polymorphisms difference, same antibiotic and heavy metal resistance genes, virulence genes, and plasmids) were found in faeces of dogs, cattle, or sheep from the same farm, and in a dog and a wild rodent living in proximity. CONCLUSIONS: To our knowledge, this is the first report of multiple clonal cross-species transmission of ESBL-E. coli in domestic and potentially wild animals of Latin America. Our results suggest that relatively rare spread of AMR across animal species can still occur by both clonal and plasmid dissemination. Our study highlights the need for establishing preventive measures to limit the circulation of these bacteria among animals in agricultural settings, particularly given the highly pathogenic profile of several E. coli strains detected in these animals.

Validation of a Pathological Score for the Assessment of Bronchial Biopsies in Severe Uncontrolled Asthma: Beyond Blood Eosinophils.

BACKGROUND: Blood eosinophil count (BEC) is currently used as a surrogate marker of T2 inflammation in severe asthma but its relationship with tissue T2-related changes is elusive. Bronchial biopsy could add reliable information but lacks standardization. OBJECTIVES: To validate a systematic assessment of the bronchial biopsy for the evaluation of severe uncontrolled asthma (SUA) by standardizing a pathological score. METHODS: A systematic assessment of submucosal inflammation, tissue eosinophilic count/field (TEC), goblet cells hyperplasia, epithelial changes, basement membrane thickening, prominent airway smooth muscle and submucosal mucous glands was initially agreed and validated in representative bronchial biopsies of 12 patients with SUA by 8 independent pathologists. In a second phase, 62 patients with SUA who were divided according to BEC≥300cells/mm3 or less underwent bronchoscopy with bronchial biopsies and the correlations between the pathological findings and the clinical characteristics were investigated. RESULTS: The score yielded good agreement among pathologists regarding submucosal eosinophilia, TEC, goblet cells hyperplasia and mucosal glands (ICC=0.85, 0.81, 0.85 and 0.87 respectively). There was a statistically significant correlation between BEC and TEC (r=0.393, p=0.005) that disappeared after correction by oral corticosteroids (OCS) use (r=0.170, p=0.307). However, there was statistically significant correlation between FeNO and TEC (r=0.481, p=0.006) that was maintained after correction to OCS use (r=0.419, p=0.021). 82.4% of low-BEC had submucosal eosinophilia, 50% of them moderate to severe. CONCLUSION: A standardized assessment of endobronchial biopsy is feasible and could be useful for a better phenotyping of SUA especially in those receiving OCS.

A Phase I Study of Ex Vivo Expanded Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells for the Treatment of Pediatric Perianal Fistulizing Crohn's Disease.

BACKGROUND: Perianal fistulizing Crohn's disease is notoriously difficult to treat. Recent studies of mesenchymal stem cells have demonstrated safety and efficacy of this novel treatment approach. However, no studies to date have included pediatric patients. We sought to determine safety and efficacy of mesenchymal stem cells for pediatric perianal fistulizing Crohn's disease. METHODS: This was a phase I clinical trial to evaluate safety and feasibility of mesenchymal stem cells in pediatric perianal Crohn's patients 13 to 17 years of age. At the time of an exam under anesthesia, following curettage of the fistula tract and closure of the internal opening with absorbable suture, 75 million mesenchymal stem cells were administered with a 22-gauge needle. This was repeated at 3 months if complete clinical and radiographic healing were not achieved. Adverse and serious adverse events at were measured at postprocedure day 1, week 2, week 6, month 3, month 6, and month 12. Clinical healing, radiographic healing per magnetic resonance imaging, and patient-reported outcomes were measured at the same time points. RESULTS: Seven pediatric patients were enrolled and treated (6 male; median age of 16.7 years). There were no adverse or serious adverse events related to the investigational product or injection procedure. At 6 months, 83% had complete clinical and radiographic healing. The perianal Crohn's Disease Activity Index, Wexner incontinence score, and Van Assche score had all decreased at 6 months. CONCLUSIONS: Bone marrow-derived mesenchymal stem cells offer a safe, and likely effective, treatment approach for pediatric perianal fistulizing Crohn's disease.

Riesgo hemorrágico y embólico de los pacientes con fibrilación auricular y cáncer / Bleeding and embolic risk in patients with atrial fibrillation and cancer

Introducción y objetivos El impacto del cáncer en los eventos de los pacientes con fibrilación auricular (FA) no está claro. El objetivo de este estudio es evaluar cómo el cáncer influye en el riesgo de eventos embólicos y hemorrágicos de los pacientes con FA. Métodos Conformaron la población del estudio 16.056 pacientes de un área sanitaria española diagnosticados de FA entre 2014 y 2018. De ellos, 1.137 (7,1%) tenían antecedentes de cáncer. Durante una mediana de seguimiento de 4,9 años, se evaluó mediante un análisis de riesgos competitivos la relación entre el cáncer y las embolias y hemorragias. Resultados No se detectó asociación entre un mayor riesgo de eventos embólicos y cáncer en general (sHR=0,73; IC95%, 0,41-1,26). Sin embargo, el cáncer se asoció con un mayor riesgo hemorrágico, aunque solo en pacientes con cáncer activo (sHR=1,42; IC95%, 1,20-1,67) o radioterapia previa (sHR=1,40; IC95%, 1,19-1,65). Las escalas CHA2DS2-VASc y HAS-BLED mostraron un rendimiento subóptimo para predecir el riesgo, respectivamente, embólico y hemorrágico (estadístico c <0,50) de los pacientes no anticoagulados con cáncer activo. La relación entre el aumento de las hemorragias y la disminución de las embolias con anticoagulación fue similar en pacientes con y sin cáncer (5,6 frente a 7,8; p <0,001). Conclusiones El cáncer no se asoció con un mayor riesgo de eventos embólicos en pacientes con FA, solo con un mayor riesgo de hemorragia. Sin embargo, el cáncer activo empeoró la capacidad predictiva de las escalas CHA2DS2-VASc y HAS-BLED para predecir eventos en pacientes no anticoagulados (AU)

Introduction and objectives The impact of cancer on clinical outcomes in patients with atrial fibrillation (AF) is unclear. The aim of this study was to assess how cancer influences the prediction and risk of embolic and hemorrhagic events in patients with AF. Methods The study population comprised 16 056 patients from a Spanish health area diagnosed with AF between 2014 and 2018. Of these, 1137 (7.1%) had a history of cancer. During a median follow-up of 4.9 years, we assessed the relationship between cancer and bleeding and embolic events by competing risk analysis, considering death as a competing risk. Results No association was detected between an increased risk of embolic events and cancer overall (sHR, 0.73; 95%CI, 0.41-1.26), active cancer, or any subgroup of cancer. However, cancer was associated with an increased risk of bleeding, although only in patients with active cancer (sHR, 1.42; 95%CI, 1.20-1.67) or prior radiotherapy (sHR, 1.40; 95%CI, 1.19-1.65). Both the CHA2DS2-VASc and HAS-BLED scores showed suboptimal performance to predict embolic and bleeding risk (c-statistic <0.50), respectively, in nonanticoagulated patients with active cancer. The ratio between the increase in bleeding and the decrease in embolisms with anticoagulation was similar in patients with and without cancer (5.6 vs 7.8; P <.001). Conclusions Cancer was not associated with an increased risk of embolic events in AF patients, only with an increased risk of bleeding. However, active cancer worsened the ability of the CHA2DS2-VASc and HAS-BLED scores to predict embolic and bleeding events, respectively, in nonanticoagulated patients (AU)

Phytochemicals Determination, and Antioxidant, Antimicrobial, Anti-Inflammatory and Anticancer Activities of Blackberry Fruits.

A comprehensive characterization of the phytochemicals present in a blackberry fruit extract by HPLC-TOF-MS has been carried out. The main compounds in the extract were ursane-type terpenoids which, along with phenolic compounds, may be responsible for the bioactivity of the extract. In vitro antioxidant capacity was assessed through Folin-Ciocalteu (31.05 ± 4.9 mg GAE/g d.w.), FRAP (637.8 ± 3.2 µmol Fe2+/g d.w.), DPPH (IC50 97.1 ± 2.4 µg d.w./mL) and TEAC (576.6 ± 8.3 µmol TE/g d.w.) assays. Furthermore, the extract exerted remarkable effects on in vitro cellular antioxidant activity in HUVEC cells at a concentration of 5 mg/mL. Antimicrobial activity of the extract was also tested. Most sensible microorganisms were Gram-positive bacteria, such as E. faecalis, B. cereus and Gram-negative E. coli (MBC of 12.5 mg/mL). IC50 values against colon tumoral cells HT-29 (4.9 ± 0.2 mg/mL), T-84 (5.9 ± 0.3 mg/mL) and SW-837 (5.9 ± 0.2 mg/mL) were also obtained. Furthermore, blackberry extract demonstrated anti-inflammatory activity inhibiting the secretion of pro-inflammatory IL-8 cytokines in two cellular models (HT-29 and T-84) in a concentration-dependent manner. These results support that blackberry fruits are an interesting source of bioactive compounds that may be useful in the prevention and treatment of different diseases, mainly related to oxidative stress.

Word of caution: Rectal cancer without response to neoadjuvant treatment - Do not wait for surgery.

BACKGROUND: We hypothesized that prolonging the interval to surgery in non-responders to neoadjuvant chemoradiation therapy (nCRT) could lead to worse oncologic outcomes. METHODS: Rectal adenocarcinoma patients with poor tumor response to nCRT (AJCC tumor regression grade 3) were selected. Oncologic outcomes were evaluated according to the time interval between completion of nCRT and surgery. RESULTS: Among 56 non-responders, 28 patients surgically treated ≥8 weeks after completion of nCRT had worse disease-free survival (31% vs. 49%, p â€‹= â€‹0.05) and worse overall survival (34% vs. 53%, p â€‹= â€‹0.02) compared to patients <8 weeks. Using the three different intervals (≥12 weeks, 6-12 weeks, and< 6 weeks), waiting longer was consistently associated with worse overall (23% vs. 48% vs. 63%, p â€‹= â€‹0.02) and worse cancer-specific survival (35% vs. 61% vs. 71%, p â€‹= â€‹0.04), respectively. CONCLUSION: For rectal cancer patients who are non-responders to nCRT, delay of surgery may lead to worse oncologic outcomes.

Establishment of a Sonotrode Extraction Method and Evaluation of the Antioxidant, Antimicrobial and Anticancer Potential of an Optimized Vaccinium myrtillus L. Leaves Extract as Functional Ingredient.

Vaccinium myrtillus L. (bilberry) leaves are an important by-product of berry production that may be used as a source of phenolic compounds which have a positive effect on human health. Therefore, an ultrasound-assisted extraction via sonotrode has been used for the first time to recover bioactive compounds from bilberry leaves. The extraction has been optimized using a Box-Behnken design. The influence of ethanol:water ratio (v/v), time of extraction (min) and amplitude (%) were evaluated considering total phenolic content (TPC) and antioxidant capacity (DPPH and FRAP assays) as dependent variables in a response surface methodology (RSM). Optimum values for the independent factors were 30:70 ethanol/water (v/v), 5 min of extraction and 55% amplitude. The empirical values of the independent variables using the optimized conditions were 217.03 ± 4.92 mg GAE/g d.w. (TPC), 271.13 ± 5.84 mg TE/g d.w. (DPPH) and 312.21 ± 9.30 mg TE/g d.w. (FRAP). The validity of the experimental design was confirmed using ANOVA and the optimal extract was characterized using HPLC-MS. A total of 53 compounds were tentatively identified, of which 22 were found in bilberry leaves for the first time. Among them, chlorogenic acid was the most abundant molecule, representing 53% of the total phenolic compounds identified. Additionally, the antimicrobial and anticancer activities of the optimum extract were tested. Gram-positive bacteria demonstrated high sensitivity to bilberry leaves extract in vitro, with MBC values of 6.25 mg/mL for Listeria monocytogenes, Listeria innocua and Enterococcus faecalis, and 0.8 mg/mL for Staphylococcus aureus and Bacillus cereus. Furthermore, bilberry leaves extract exerted in vitro antiproliferative activity against HT-29, T-84 and SW-837 colon tumor cells with IC50 values of 213.2 ± 2.5, 1140.3 ± 5.2 and 936.5 ± 4.6 µg/mL, respectively. Thus, this rapid ultrasound-assisted extraction method has demonstrated to be an efficient technique to obtain bilberry leaves extract with in vitro antioxidant, antimicrobial and anticancer capacities that may be useful for the food industry as natural preservative or even for the production of functional foods or nutraceuticals.

Evaluating the functional, sexual and seasonal variation in the chemical constituents from feces of adult Iberian wolves (Canis lupus signatus).

Chemical signals deposited in feces play an important role in intraspecific and interspecific communication of many mammals. We collected fresh feces of adult wolves from wild breeding groups. All samples visually identified as belonging to wolves were subsequently identified to species level by sequencing a small fragment of mtDNA and sexed typing DBX6 and DBY7 sex markers. Using gas chromatography-mass spectrometry (GC-MS), we identified 56 lipophilic compounds in the feces, mainly heterocyclic aromatic organic compounds, such as indole or phenol, but also steroids, such as cholesterol, carboxylic acids and their esters between n-C4 and n-C18, aldehydes, alcohols and significant quantities of squalene and α-tocopherol, which would increase the chemical stability of feces on humid substrates. There was variability in the number and proportions of compounds between sexes, which could be indicative of their function as chemical signals. We also found variability in different reproductive states, especially in odorous compounds, steroids and α-tocopherol. Feces with a presumed marking function had higher proportions of α-tocopherol and steroids than feces with non-marking function. These compounds could be involved in intragroup and intergroup communication of wolves and their levels in feces could be directly related with the wolf's sex and physiological and reproductive status.